In many brain regions, electrical coupling, mediated primarily by Cx36 gap junctions, contributes to neuronal plasticity. In the retina, gap junctions are particularly abundant and they play a key role in the switch from rod to cone pathways. This is an important example of neuronal plasticity that makes the retina a useful system to study gap junction modulation. The mammalian retina detects light over an enormous range of intensities, approximately 12 log units. Furthermore, there are distinct pathways through the retina for both rod and cone signals, in part mediated by gap junction connections. The goal of this research is to test rod and cone connections and determine the physiological role of gap junctions in rod and cone pathways. Specific Aim1 is to map the connections of rods and cones to bipolar cells. By filling single rod bipolar cells in rabbit, we can determine their rod or cone contacts unambiguously. Most ON cone bipolar cells can be labeled via their coupling with AII amacrine cells, providing a novel way to view ON bipolar connections with rods and cones. Controversial results from mouse retina suggested two types of rod bipolar cell (RBC), one of which receives cone input. We will test this hypothesis by recording from mouse bipolar cells and correlating physiology with confocal analysis of rod/cone contacts.
In Specific Aim 2, the working hypothesis is that there are 3 kinds of photoreceptor coupling, cone/cone, rod/cone and rod/rod, all using Cx36. Taking a transgenic approach, using rod-specific and cone- specific Cx36 KO mice, we will correlate single photon responses in rods with Neurobiotin coupling patterns and the distribution of Cx36 gap junctions. This will identify the rod connexin and establish the physiological role of Cx36 in rod/rod and rod/cone coupling. Specific Aim 3. AII amacrine cells are a well-known example of well-coupled network. Plasticity in this network is responsible for major changes in retinal circuitry underlying the switch from rod to cone pathways. There is circumstantial evidence that dopamine modulates AII coupling but no direct physiological evidence. We have developed a novel technique in mouse retinal slices to estimate AII network coupling. We have validated this approach using gap junction antagonists and Cx36 KO mice. Here, we report for the first time that dopamine modulates electrical coupling in the AII network. The mammalian retina is a self-optimizing network of around seventy different neuronal cell types. The retina detects light but in addition it is continually adjusting to the intensity and pattern of the visual scene to provide the best output. It is important to understand the structure and function of retinal circuits. Such knowledge will be required to test if transplanted or regenerated cells form appropriate functional connections.

Public Health Relevance

The mammalian retina is an engineering marvel that not only detects light but it is continually adjusting to the intensity and pattern of the visual scene to provide the best output. Well-known examples of this self-optimizing network are dark adaptation and color after images. Furthermore, there are distinct pathways through the retina for both rod and cone signals, some mediated by electrical connections known as gap junctions. It is important to understand the structure and function of retinal circuits in vision. Such knowledge will be required to test if transplanted or regenerated cells form appropriate connections.